Currently, 50% of patients who have undergone post-prostatectomy radiotherapy after PSA failure manifest subsequent systemic disease. Compared to PET/CT with molecular radiotracers, conventional imaging methods fall short in identifying sites of prostate cancer recurrence. Our goal is to address an unmet public health need by improving long term biochemical control of patients with recurrent prostate carcinoma. We have verified a key scientific premise that advanced molecular imaging with the synthetic amino acid PET radiotracer fluciclovine (18F) (anti-3-[18F]FACBC) results in significantly greater disease detection, with a 40.5% change in management and 83.6% change in planning volumes (without dose escalation) compared with conventional imaging. During the course of our trial, and in large part because of our translational work, fluciclovine (18F) was FDA approved in 2016 for recurrent prostate cancer, contributing to a new standard of care. As of Version 1.2018, fluciclovine (18F) has now been included in the National Comprehensive Cancer Network (NCCN) Guidelines for restaging recurrent prostate cancer. Moreover, salvage radiotherapy is being offered at increasingly lower PSA levels, and evidence is accumulating that boosting radiotherapy dose to foci of active disease may result in clinical benefit. Preliminary analysis of still accruing data from our ongoing clinical trial (5R01CA129356: NCT01666808) suggests that integrating fluciclovine may result in a small improvement in failure rate, but not have adequate sensitivity to definitively achieve durable PSA control with standard radiotherapy doses. Yet, there is early evidence that a new class of PET radiotracer targeting the prostate specific membrane antigen (PSMA) receptor may have greater sensitivity at lower PSA levels for disease detection. Gallium-68 (68Ga) PSMA is one such PSMA PET ligand, though not FDA approved. Each class of PET radiotracer, amino acid metabolic (fluciclovine) vs receptor based (PSMA), exhibits advantages and disadvantages. Our hypothesis is that by utilizing a higher affinity PET ligand, we can better select and manage patients who will benefit from salvage radiotherapy undertaken at lower PSA levels. In addition, we hypothesize that by dose escalating targets identified with either fluciclovine (18F) or 68Ga PSMA, we will determine if dose escalation in itself provides improved PSA control. To test these hypotheses with the highest scientific rigor, we will conduct a prospective clinical trial in which patients who are eligible for salvage radiotherapy are randomized to either fluciclovine (18F) or 68Ga PSMA PET/CT. We will explore if positive specific tissue biomarker signatures may be useful to help predicts post-prostatectomy radiotherapy outcomes in combination with the standard risk criteria. Our proposal is timely since recent editorials in the literature regarding salvage radiotherapy post-prostatectomy call for integration of molecular imaging in prospective, randomized, controlled trials with toxicity analyses of the type we will carry out.